Citation:

Miller, C., E. Stewart, Mette C. Schladweiler, J. Richards, P. Phillips, K. McDaniel, C. Gordon, U. Kodavanti, AND J. Dye. Both sex and prenatal ozone exposure programs hepatic sensitivity to a high-fat diet in the adolescent rat. Society of Toxicology Virtual Meeting, NA, March 12 - 21, 2021.

Impact/Purpose:

Altered fetal weight gain is a hypothesized contributing factor in the increasing prevalence of adult cardiometabolic disease by modulating the sensitivity to a poor diet. To investigate this phenomenon in our model of O3-induced growth restriction, pregnant Long-Evans rats were exposed to 0.8 ppm O3 or filtered air during gestational days 5 and 6 (4 hr/d). In adolescence, male and female offspring were fed a 3-day high-fat diet (HFD) to assess their metabolic flexibility.

Description:

Acute exposure to ozone (O3) during implantation receptivity impairs fetal growth in both male and female offspring. Altered fetal weight gain is a hypothesized contributing factor in the increasing prevalence of adult cardiometabolic disease by modulating the sensitivity to a poor diet. To investigate this phenomenon in our model of O3-induced growth restriction, pregnant Long-Evans rats were exposed to 0.8 ppm O3 or filtered air during gestational days 5 and 6 (4 hr/d). In adolescence, male and female offspring were fed a 3-day high-fat diet (HFD) to assess their metabolic flexibility. In offspring from O3-exposed dams, HFD increased caloric intake and reduced energy expenditure in both sexes. In males, this caloric imbalance resulted in reduced hepatic triglycerides, increased circulating cholesterol, and increased body adiposity. Such extrahepatic lipid mobilization was not prevalent in the female offspring (O3+HFD). Postnatal HFD challenge in female offspring from O3-exposed dams altered the expression of genes related to insulin signaling, gluconeogenesis, lipolysis, and genes involved in both the signaling and regulation of bile acid status in the liver. Ingenuity Pathway Analysis in the hepatic gene set reported Hepatic Cholestasis, FXR/RXR Signaling, and AMPK Signaling as top canonical pathways altered. Unlike in the male offspring, females were unable to activate AMPK phosphorylation, increase Sirtuin 1, or reduce p300 in the liver after three days of HFD, highlighting a potential divergence in the hepatic metabolic response to HFD between the sexes. Together, these findings demonstrate that acute exposure to ozone early in pregnancy programs the postnatal susceptibility to a calorically dense diet high in saturated fat. However, the specific impacts of this appear to be driven by sex differences in hepatic metabolism in the offspring. [Does not reflect US EPA policy]

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